mBio. 2021 Aug 10:e0182321. doi: 10.1128/mBio.01823-21. Online ahead of print.

ABSTRACT

Bacteria in the Burkholderia cepacia complex (BCC) are significant pathogens for people with cystic fibrosis (CF) and are often extensively antibiotic resistant. Here, we assess the impacts of clinically observed mutations in fixL, which encodes the sensor histidine kinase FixL. FixL along with FixJ compose a two-component system that regulates multiple phenotypes. Mutations in fixL across two species, B. dolosa and B. multivorans, have shown evidence of positive selection during chronic lung infection in CF. Herein, we find that BCC carrying the conserved, ancestral fixL sequence have lower survival in macrophages and in murine pneumonia models than mutants carrying evolved fixL sequences associated with clinical decline in CF patients. In vitro phosphotransfer experiments found that one evolved FixL protein, W439S, has a reduced ability to autophosphorylate and phosphorylate FixJ, while LacZ reporter experiments demonstrate that B. dolosa carrying evolved fixL alleles has reduced fix pathway activity. Interestingly, B. dolosa carrying evolved fixL alleles was less fit in a soil assay than those strains carrying the ancestral allele, demonstrating that increased survival of these variants in macrophages and the murine lung comes at a potential expense in their environmental reservoir. Thus, modulation of the two-component system encoded by fixLJ by point mutations is one mechanism that allows BCC to adapt to the host infection environment. IMPORTANCE Infections caused by members of the Burkholderia cepacia complex (BCC) are a serious concern for patients with cystic fibrosis (CF) as these bacteria are often resistant to many antibiotics. During long-term infection of CF patients with BCC, mutations in genes encoding the FixLJ system often become prevalent, suggesting that these changes may benefit the bacteria during infection. The system encoded by fixLJ is involved in sensing oxygen and regulating many genes in response and is required for full virulence of the bacteria in a murine pneumonia model. Evolved fixL mutations seen later in infection improve bacterial persistence within macrophages and enhance infection within mice. However, these adaptations are short sighted because they reduce bacterial fitness within their natural habitat, soil.

PMID:34372701 | DOI:10.1128/mBio.01823-21

Viruses. 2021 Jul 9;13(7):1331. doi: 10.3390/v13071331.

ABSTRACT

The increasing prevalence and worldwide distribution of multidrug-resistant bacterial pathogens is an imminent danger to public health and threatens virtually all aspects of modern medicine. Particularly concerning, yet insufficiently addressed, are the members of the Burkholderia cepacia complex (Bcc), a group of at least twenty opportunistic, hospital-transmitted, and notoriously drug-resistant species, which infect and cause morbidity in patients who are immunocompromised and those afflicted with chronic illnesses, including cystic fibrosis (CF) and chronic granulomatous disease (CGD). One potential solution to the antimicrobial resistance crisis is phage therapy-the use of phages for the treatment of bacterial infections. Although phage therapy has a long and somewhat checkered history, an impressive volume of modern research has been amassed in the past decades to show that when applied through specific, scientifically supported treatment strategies, phage therapy is highly efficacious and is a promising avenue against drug-resistant and difficult-to-treat pathogens, such as the Bcc. In this review, we discuss the clinical significance of the Bcc, the advantages of phage therapy, and the theoretical and clinical advancements made in phage therapy in general over the past decades, and apply these concepts specifically to the nascent, but growing and rapidly developing, field of Bcc phage therapy.

PMID:34372537 | DOI:10.3390/v13071331

Mol Ther. 2021 Aug 6:S1525-0016(21)00401-9. doi: 10.1016/j.ymthe.2021.08.007. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa (P.a) infections are a major public health issue in ventilator-associated pneumoniae, cystic fibrosis and chronic obstructive pulmonary disease exacerbations. P.a is multidrug resistant and there is an urgent need to develop new therapeutic approaches. Here, we evaluated the effect of direct pulmonary transplantation of gene-modified (elafin and IL-6) syngeneic macrophages in a mouse model of acute of P.a infection. Wild type (WT) or Elafin-transgenic (eTg) alveolar macrophages (AMs) or bone marrow derived macrophages (BMDMs) were recovered from broncho-alveolar lavage or generated from WT or eTg mice bone marrow. Cells were modified with adenovirus IL-6 (Ad-IL6), characterized in vitro and transferred by oropharyngeal instillation in the lungs of naïve mice. The protective effect was assessed during P.a acute infection (survival studies, mechanistic studies of the inflammatory response). We show that a single bolus of syngeneic AMs or BMDMs genetically modified provided protection in our pneumonia P.a-induced model. Mechanistically, Elafin-modified AMs had an IL-6-IL-10-IL-4R-IL-22-antimicrobial molecular signature which, in synergy with IL-6, enhanced epithelial cell proliferation and tissue repair in the alveolar unit. We believe that this innovative cell therapy strategy could be of value in acute bacterial infections in the lung.

PMID:34371178 | DOI:10.1016/j.ymthe.2021.08.007

Antimicrob Agents Chemother. 2021 Aug 9:AAC0133221. doi: 10.1128/AAC.01332-21. Online ahead of print.

ABSTRACT

The Burkholderia cepacia complex (Bcc) and Burkholderia gladioli are opportunistic pathogens that most commonly infect persons with cystic fibrosis or compromised immune systems. Members of the Burkholderia genus are intrinsically multidrug resistant (MDR), possessing both a PenA carbapenemase and an AmpC β-lactamase, which renders treatment of infection due to these species problematic. Here, we tested the β-lactam-β-lactamase inhibitor combination, imipenem-relebactam, against a panel of MDR Bcc and B. gladioli. The addition of relebactam to imipenem dramatically lowered the MICs for Bcc and B. gladioli with only 16% of isolates testing susceptible to imipenem vs. 71.3% being susceptible to the imipenem-relebactam combination. While ceftazidime-avibactam remained the most potent combination drug against this panel of Bcc and B. gladioli, imipenem-relebactam was active against 71.4% of the ceftazidime-avibactam-resistant isolates. Relebactam demonstrated potent inactivation of the Burkholderia multivorans PenA1 with a Ki app value of 3.2 μM. Timed mass spectrometry revealed that PenA1 formed a very stable adduct with relebactam, without any detectable desulfation up to 24 hours. Based on our results, imipenem-relebactam may represent an alternative salvage therapy for Bcc and B. gladioli infection, especially in cases where the isolates are resistant to ceftazidime-avibactam.

PMID:34370574 | DOI:10.1128/AAC.01332-21

Physiother Theory Pract. 2021 Aug 8:1-11. doi: 10.1080/09593985.2021.1962463. Online ahead of print.

ABSTRACT

BACKGROUND: Physical activity (PA) is important in Cystic Fibrosis (CF) management. Fitness wearables are becoming increasingly popular as measurement tools of PA; however, the accuracy of these devices should first be evaluated.

OBJECTIVE: The purpose of this study was to assess the accuracy of the ActivPAL and Fitbit Charge 2 as a measure of step count in Cystic Fibrosis.

METHODS: Twenty-one participants were recruited from an adult CF Center in Ireland for a single session of testing. Participants walked for 5 min at five pre-determined speeds in a controlled testing environment (2, 2.5, 3, 3.5 and 4 miles per hour on a treadmill) and at three self-selected speeds in a corridor (slow, medium, and fast). They concurrently wore an accelerometer (ActivPAL) and fitness wearable (Fitbit Charge 2), and both were compared to visual observations. Step count is the outcome being assessed.

RESULTS: The ActivPAL under-estimated step count by 0.63% across treadmill speeds and 1.1% across self-selected walking speeds. The Fitbit Charge 2 underestimated the step count by 2.97% across treadmill speeds and by 6.3% across self-selected walking speeds. Very strong correlations were found between the ActivPAL and visual observations (r: 0.93 to 0.99), while the Fitbit Charge 2 ranged from weak to very strong correlations when compared to visual observations (r: 0.34 to 0.84).

CONCLUSION: The ActivPAL and Fitbit Charge 2 demonstrated acceptable validity for step count measurement in CF. These devices can be used for tracking PA during interventions in people with CF.

PMID:34369283 | DOI:10.1080/09593985.2021.1962463

Front Cell Infect Microbiol. 2021 Jul 23;11:698662. doi: 10.3389/fcimb.2021.698662. eCollection 2021.

ABSTRACT

Scedosporium and Lomentospora species are filamentous fungi responsible for a wide range of infections in humans and are frequently associated with cystic fibrosis and immunocompromising conditions. Because they are usually resistant to many antifungal drugs available in clinical settings, studies of alternative targets in fungal cells and therapeutic approaches are necessary. In the present work, we evaluated the in vitro antifungal activity of miltefosine against Scedosporium and Lomentospora species and how this phospholipid analogue affects the fungal cell. Miltefosine inhibited different Scedosporium and Lomentospora species at 2-4 µg/ml and reduced biofilm formation. The loss of membrane integrity in Scedosporium aurantiacum caused by miltefosine was demonstrated by leakage of intracellular components and lipid raft disorganisation. The exogenous addition of glucosylceramide decreased the inhibitory activity of miltefosine. Reactive oxygen species production and mitochondrial activity were also affected by miltefosine, as well as the susceptibility to fluconazole, caspofungin and myoricin. The data obtained in the present study contribute to clarify the dynamics of the interaction between miltefosine and Scedosporium and Lomentospora cells, highlighting its potential use as new antifungal drug in the future.

PMID:34368017 | PMC:PMC8343104 | DOI:10.3389/fcimb.2021.698662

Front Neurol. 2021 Jul 23;12:688362. doi: 10.3389/fneur.2021.688362. eCollection 2021.

ABSTRACT

Subarachnoid hemorrhage (SAH) is a devastating stroke subtype with a high rate of mortality and morbidity. The poor clinical outcome can be attributed to the biphasic course of the disease: even if the patient survives the initial bleeding emergency, delayed cerebral ischemia (DCI) frequently follows within 2 weeks time and levies additional serious brain injury. Current therapeutic interventions do not specifically target the microvascular dysfunction underlying the ischemic event and as a consequence, provide only modest improvement in clinical outcome. SAH perturbs an extensive number of microvascular processes, including the "automated" control of cerebral perfusion, termed "cerebral autoregulation." Recent evidence suggests that disrupted cerebral autoregulation is an important aspect of SAH-induced brain injury. This review presents the key clinical aspects of cerebral autoregulation and its disruption in SAH: it provides a mechanistic overview of cerebral autoregulation, describes current clinical methods for measuring autoregulation in SAH patients and reviews current and emerging therapeutic options for SAH patients. Recent advancements should fuel optimism that microvascular dysfunction and cerebral autoregulation can be rectified in SAH patients.

PMID:34367053 | PMC:PMC8342764 | DOI:10.3389/fneur.2021.688362

J Cyst Fibros. 2021 Aug 5:S1569-1993(21)01326-6. doi: 10.1016/j.jcf.2021.07.012. Online ahead of print.

ABSTRACT

BACKGROUND: Adults with cystic fibrosis (awCF) have higher levels of depression and anxiety than community samples. The Coping and Learning to Manage Stress with CF (CALM) intervention was developed for awCF reporting elevated symptoms of depression or anxiety.

METHODS: In this pilot study, awCF were randomly assigned to either six telehealth sessions (CALM; n = 15) or treatment-as-usual (TAU; n = 16). Primary outcomes were depression and anxiety. Secondary outcomes were coping self-efficacy and health-related quality of life (HrQOL). Tertiary outcomes were feasibility, acceptability, and satisfaction. Assessments were completed at baseline, post-intervention, and 3-month follow-up. Group differences were examined via independent samples t-tests. Effect size (ES) was calculated via Cohen's d to provide a measure of the magnitude of the treatment effect.

RESULTS: At post-intervention, the CALM group had a lower mean score than the TAU group for depression (medium ES) and anxiety (large ES). The CALM group had higher (i.e., better) mean scores than the TAU group for coping (large ES) and HrQOL domains of Social Functioning (large ES) and Vitality (large ES). Most treatment gains were not sustained at 3-month follow-up. CALM was feasible, requiring <12 min. for setup and scheduling, and allowed seamless participation when hospitalized. Mean scores for acceptability and satisfaction indicated that most participants either agreed or strongly agreed that CALM was acceptable and satisfactory.

CONCLUSIONS: CALM shows promise as an intervention to reduce symptoms of depression and anxiety and improve coping and HrQOL. Next steps are to add a booster session and examine CALM via a multi-site RCT.

PMID:34366282 | DOI:10.1016/j.jcf.2021.07.012

J Cyst Fibros. 2021 Aug 5:S1569-1993(21)01327-8. doi: 10.1016/j.jcf.2021.07.013. Online ahead of print.

ABSTRACT

INTRODUCTION: the effect of bone-active drugs on the risk of fragility fractures (Fx), bone mineral density (BMD) and trabecular bone score (TBS) changes in patients receiving lung transplantation (LTx) is largely unknown. This study assessed the bone-active drugs effect in patients undergoing LTx both with (CF) and without (nCF) cystic-fibrosis.

METHODS: We evaluated incident Fx, both clinical and morphometric vertebral Fx by spinal X-ray, BMD and trabecular bone score (TBS) in 117 patients (CF=50, nCF n = 67) before and 24-months after LTx. A bone-active therapy was proposed to all LTx candidates.

RESULTS: 83.8% of patients started a bone-active drug. Lumbar-spine (LS) T-score improved significantly only in treated patients (-1.4 ± 1.0 vs -2.0±1.0, p = 0.0001), whereas femur BMD and TBS remained stable in treated and not treated subjects. The rate of incident Fx was 15.3%, with no difference between treated and not treated patients. After LTx, LS T-score improved significantly only in nCF group (-1.3 ± 1.0 vs -1.8 ± 1.1, p = 0.0001), while femur remained stable in both nCF and CF groups. Patients with CF showed a significant Z-TBS increase (-3.6 ± 1.7 vs -3.0 ± 1.7, p = 0.019) and a lower Fx incidence as compared with nCF patients (4.1% vs 24.2%, p =0.003). Incident Fx were associated with nCF diagnosis (OR 7.300, CI95% 1.385-38.461, p = 0.019) regardless of prevalent Fx, previous glucocorticoid therapy and bone-active therapy introduced at least 6 months before LTx.

CONCLUSIONS: A prompt medical intervention helps in preventing BMD loss after LTx. As compared with nCF patients, CF patients show a TBS increase and a lower Fx risk after LTx.

PMID:34366281 | DOI:10.1016/j.jcf.2021.07.013

J Cyst Fibros. 2021 Aug 4:S1569-1993(21)01335-7. doi: 10.1016/j.jcf.2021.07.016. Online ahead of print.

NO ABSTRACT

PMID:34364815 | DOI:10.1016/j.jcf.2021.07.016

Sci Rep. 2021 Aug 6;11(1):16001. doi: 10.1038/s41598-021-95364-1.

ABSTRACT

This paper presents a fully automatic and end-to-end optimised airway segmentation method for thoracic computed tomography, based on the U-Net architecture. We use a simple and low-memory 3D U-Net as backbone, which allows the method to process large 3D image patches, often comprising full lungs, in a single pass through the network. This makes the method simple, robust and efficient. We validated the proposed method on three datasets with very different characteristics and various airway abnormalities: (1) a dataset of pediatric patients including subjects with cystic fibrosis, (2) a subset of the Danish Lung Cancer Screening Trial, including subjects with chronic obstructive pulmonary disease, and (3) the EXACT'09 public dataset. We compared our method with other state-of-the-art airway segmentation methods, including relevant learning-based methods in the literature evaluated on the EXACT'09 data. We show that our method can extract highly complete airway trees with few false positive errors, on scans from both healthy and diseased subjects, and also that the method generalizes well across different datasets. On the EXACT'09 test set, our method achieved the second highest sensitivity score among all methods that reported good specificity.

PMID:34362949 | DOI:10.1038/s41598-021-95364-1

Ital J Pediatr. 2021 Aug 6;47(1):168. doi: 10.1186/s13052-021-01117-1.

ABSTRACT

Cystic fibrosis (CF) is a multisystem disorder, caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. These cause a reduced secretion of chloride, a marked absorption of sodium and, therefore, of water, through the epithelium, resulting in the formation of thickened secretions in organs such as lung or pancreas. These viscous secretions lead to airway obstruction, chronic infection and inflammation resulting in progressive lung damage, bronchiectasis and eventual respiratory failure. Although the average life expectancy has increased over the last 30 years, lung disease is the most common cause of death in people with CF. For these reasons, the improvement of sputum clearance is a major therapeutic aim in CF and early initiation of airway clearance is widely recommended and implemented. Symptomatic mucolytic therapy today is mainly based on inhalation of DNase, hypertonic saline or mannitol, in combination with physiotherapy. Mucolytic agents break down the gel structure of mucus and therefore decrease its elasticity and viscosity, reducing the pulmonary exacerbation frequency and to improve and stabilize lung function. Nevertheless, high quality studies comparing these mucolytic drugs are still few, and the individual experiences of patients and caregivers explain the high variability of their use globally. This review will summarize the current knowledge on hypertonic saline in the treatment of CF lung disease. Furthermore, we report the real-world prescription of inhaled mucolytic agents in CF.

PMID:34362426 | DOI:10.1186/s13052-021-01117-1

Pharm Biol. 2021 Dec;59(1):1008-1015. doi: 10.1080/13880209.2021.1949357.

ABSTRACT

CONTEXT: Cucumber (Cucumis sativus Linn. [Cucurbitaceae]) is widely known for its purgative, antidiabetic, antioxidant, and anticancer therapeutic potential. However, its effect on gastrointestinal (GI) disease is unrecognised.

OBJECTIVE: This study investigated the effect of C. sativus fruit extract (CCE) on intestinal chloride secretion, motility, and motor function, and the role of TMEM16A chloride channels.

MATERIALS AND METHODS: CCE extracts were obtained from commercially available cucumber. Active fractions were then purified by HPLC and analysed by high resolution mass spectrometry. The effect of CCE on intestinal chloride secretion was investigated in human colonic T84 cells, ex vivo mouse intestinal tissue using an Ussing chamber, and the two-electrode voltage-clamp technique to record calcium sensitive TMEM16A chloride currents in Xenopus laevis oocytes. In vivo, intestinal motility was investigated using the loperamide-induced C57BL/6 constipation mouse model. Ex vivo contractility of mouse colonic smooth muscles was assessed by isometric force measurements.

RESULTS: CCE increased the short-circuit current (ΔIsc 34.47 ± µA/cm2) and apical membrane chloride conductance (ΔICl 95 ± 8.1 µA/cm2) in intestinal epithelial cells. The effect was dose-dependent, with an EC50 value of 0.06 µg/mL. CCE stimulated the endogenous TMEM16A-induced Cl- current in Xenopus laevis oocytes. Moreover, CCE increased the contractility of smooth muscle in mouse colonic tissue and enhanced small bowel transit in CCE treated mice compared to loperamide controls. Mass spectrometry suggested a cucurbitacin-like analogue with a mass of 512.07 g/mol underlying the bioactivity of CCE.

CONCLUSION: A cucurbitacin-like analog present in CCE activates TMEM16A channels, which may have therapeutic potential in cystic fibrosis and intestinal hypodynamic disorders.

PMID:34362288 | DOI:10.1080/13880209.2021.1949357

J Clin Med. 2021 Jul 28;10(15):3316. doi: 10.3390/jcm10153316.

ABSTRACT

Assessing disease severity in patients with cystic fibrosis (CF) is essential when directing therapies. Serum immunoglobulin G (IgG) levels increase with disease severity. Lung clearance index (LCI) is recognized as an outcome measure for CF clinical trials. Our aim was to evaluate the correlations between IgG and disease severity markers. This was a single-center retrospective study, evaluating association between IgG and markers of severity in CF patients (including clinical characteristics, lung spirometry, LCI, clinical scores and computed tomography (CT) scores) during stable conditions. There were 69 patients, age 20.5 ± 11.6 years. Nineteen (27.5%) patients had elevated IgG. IgG correlated positively with LCI (r = 0.342, p = 0.005). IgG was higher in pancreatic insufficient (PI) and patients with liver disease (1504.3 ± 625.5 vs. 1229 ± 276.1 mg/dL in PI vs. PS, p = 0.023, and 1702.6 ± 720.3 vs. 1256.2 ± 345.5 mg/dL with vs. without liver disease, p = 0.001, respectively). IgG also correlated positively with CRP, CT score, and days with antibiotics in the previous year (r = 0.38, p = 0.003; r = 0.435, p = 0.001; and r = 0.361, p = 0.002, respectively), and negatively with FEV1% and SK score (r = -0.527, p < 0.001 and r = -0.613, p < 0.001, respectively). IgG correlated with clinical parameters, pulmonary functions, and imaging. However, this is still an auxiliary test, complementing other tests, including lung function and imaging tests. Larger multi-center longitudinal studies are warranted.

PMID:34362100 | DOI:10.3390/jcm10153316

Int J Mol Sci. 2021 Jul 22;22(15):7852. doi: 10.3390/ijms22157852.

ABSTRACT

Activation of the Ca2+ activated Cl- channel TMEM16A is proposed as a treatment in inflammatory airway disease. It is assumed that activation of TMEM16A will induce electrolyte secretion, and thus reduce airway mucus plugging and improve mucociliary clearance. A benefit of activation of TMEM16A was shown in vitro and in studies in sheep, but others reported an increase in mucus production and airway contraction by activation of TMEM16A. We analyzed expression of TMEM16A in healthy and inflamed human and mouse airways and examined the consequences of activation or inhibition of TMEM16A in asthmatic mice. TMEM16A was found to be upregulated in the lungs of patients with asthma or cystic fibrosis, as well as in the airways of asthmatic mice. Activation or potentiation of TMEM16A by the compounds Eact or brevenal, respectively, induced acute mucus release from airway goblet cells and induced bronchoconstriction in mice in vivo. In contrast, niclosamide, an inhibitor of TMEM16A, blocked mucus production and mucus secretion in vivo and in vitro. Treatment of airway epithelial cells with niclosamide strongly inhibited expression of the essential transcription factor of Th2-dependent inflammation and goblet cell differentiation, SAM pointed domain-containing ETS-like factor (SPDEF). Activation of TMEM16A in people with inflammatory airway diseases is likely to induce mucus secretion along with airway constriction. In contrast, inhibitors of TMEM16A may suppress pulmonary Th2 inflammation, goblet cell metaplasia, mucus production, and bronchoconstriction, partially by inhibiting expression of SPDEF.

PMID:34360618 | DOI:10.3390/ijms22157852

Int J Pharm. 2021 Aug 3:120974. doi: 10.1016/j.ijpharm.2021.120974. Online ahead of print.

ABSTRACT

Non-cystic fibrosis bronchiectasis (NCFB) is a chronic respiratory disease, and the thick and viscous mucus covering on respiratory epithelia can entrap the inhaled drugs, resulting in compromised therapeutic efficiency. In order to solve this problem, the inhalable ciprofloxacin hydrochloride microparticles (CMs) based on silk fibroin (SF) and mannitol (MAN) were designed and developed. SF was applied to increase the loading efficiency of ciprofloxacin hydrochloride by strong electrostatic interactions. MAN could facilitate the penetration of drugs through mucus, which ensured the drugs could reach their targets before clearance. Furthermore, the aerodynamic performance of the inhalable microparticles could be tuned by changing the surface roughness to achieve a high fine particle fraction value (45.04%). The antibacterial effects of CMs were also confirmed by measuring the minimum inhibitory concentration against four different bacteria strains. Moreover, a series of experiments both in vitro and in vivo showed that CMs would not affect the lung function and induce the secretion of inflammatory cytokines in lungs, demonstrating their excellent biocompatibility and biosafety. Therefore, CMs might be a promising pulmonary drug delivery system for the treatment of NCFB.

PMID:34358540 | DOI:10.1016/j.ijpharm.2021.120974

Pathogens. 2021 Jul 10;10(7):871. doi: 10.3390/pathogens10070871.

ABSTRACT

The usage of bottled water dispensers (BWDs) has spread worldwide. Despite their popularity, few studies have dealt with their microbial contaminants, and little attention is given to their fungal contamination. To our knowledge this is the first mycological study of BWDs in Europe. 36 devices have been examined in Budapest, Hungary. Despite of the strictly regulated water hygiene system in Hungary, molds and yeasts were detected in 86.8% of the samples, 56.76% were highly contaminated. Elevated heterotrophic plate counts were also observed in all samples compared to that of Hungarian drinking water. As all physical and chemical water quality characteristics have met the relevant national and European parametric values and neither totally explained the results of microbial counts, the effect of usage and maintenance habits of the devices were examined. Fungal concentrations were affected by the time elapsed since disinfection, days remaining until expiration of bottles, month of sampling and exposure to sunlight during storage. Microbes are able to proliferate in the bottled water and disperse inside the BWDs. Many of the detected fungal species (Sarocladium&nbsp;kiliense, Acremonium&nbsp;sclerotigenum/egyptiacum, Exophiala&nbsp;jeanselmei var. lecanii-corni, Exophiala&nbsp;equina, Meyerozyma&nbsp;guilliermondii, Cystobasidium&nbsp;slooffiae, Aspergillus&nbsp;jensenii, Bisifusarium&nbsp;biseptatum) are opportunistic pathogens for subpopulations of sensitive age groups and patients with immunodeficient conditions, including cystic fibrosis. Thus BWDs may pose a health risk to visitors of healthcare institutions, especially to patients with oral lesions in dental surgeries. The study draws attention to the need to investigate microbial contamination of these devices in other countries as well.

PMID:34358021 | DOI:10.3390/pathogens10070871

Pediatr Pulmonol. 2021 Aug 6. doi: 10.1002/ppul.25616. Online ahead of print.

ABSTRACT

BACKGROUND: People with cystic fibrosis (pwCF) and a minimal function (MF) mutation are poorly characterised. The aim of this study was to evaluate the disease characteristics of adult and pediatric pwCF with a genotype including an MF mutation on the basis of 2018 data from the Italian CF Registry (ICFR).

METHODS: This cross-sectional, descriptive analysis of CF disease characteristics included all of the pwCF with at least one MF mutation or two F508del (F) mutations, and at least one 2018 entry in the ICFR. Data concerning the disease characteristics of pwCF with an F/F genotype are provided for reference.

FINDINGS: A total of 5,501 pwCF had at least one entry in the 2018 ICFR, including 2,867 whose genotype included an MF mutation; in particular, 1,432 had an MF/F genotype and 1,148 the F/F genotype. The most frequent F/MF genotypes were F/N1303K (n=247, 8.6%) and F/G542X (n=193, 6.7%). The MF/no-F patients generally had a milder phenotype (a later diagnosis, lower sweat chloride levels, better nutrition, better lung function [starting from adolescence], and a lower prevalence of chronic infections and CF-related complications) than the MF/F or F/F patients.

INTERPRETATION: The findings of this descriptive analysis highlight the disease characteristics of pwCF with an MF-including genotype in Italy. The considered clinical outcomes of the pwCF with an F/MF genotype were not generally different from those of pwCF with an F/F genotype, but the patients with an MF/no-F genotype generally had a milder phenotype. This article is protected by copyright. All rights reserved.

PMID:34357699 | DOI:10.1002/ppul.25616

J Pers Med. 2021 Jul 7;11(7):643. doi: 10.3390/jpm11070643.

ABSTRACT

Trikafta, a triple-combination drug, consisting of folding correctors VX-661 (tezacaftor), VX-445 (elexacaftor) and the gating potentiator VX-770 (ivacaftor) provided unprecedented clinical benefits for patients with the most common cystic fibrosis (CF) mutation, F508del. Trikafta indications were recently expanded to additional 177 mutations in the CF transmembrane conductance regulator (CFTR). To minimize life-long pharmacological and financial burden of drug administration, if possible, we determined the necessary and sufficient modulator combination that can achieve maximal benefit in preclinical setting for selected mutants. To this end, the biochemical and functional rescue of single corrector-responsive rare mutants were investigated in a bronchial epithelial cell line and patient-derived human primary nasal epithelia (HNE), respectively. The plasma membrane density of P67L-, L206W- or S549R-CFTR corrected by VX-661 or other type I correctors was moderately increased by VX-445. Short-circuit current measurements of HNE, however, uncovered that correction comparable to Trikafta was achieved for S549R-CFTR by VX-661 + VX-770 and for P67L- and L206W-CFTR by the VX-661 + VX-445 combination. Thus, introduction of a third modulator may not provide additional benefit for patients with a subset of rare CFTR missense mutations. These results also underscore that HNE, as a precision medicine model, enable the optimization of mutation-specific modulator combinations to maximize their efficacy and minimize life-long drug exposure of CF patients.

PMID:34357110 | DOI:10.3390/jpm11070643

J Fungi (Basel). 2021 Jul 19;7(7):575. doi: 10.3390/jof7070575.

ABSTRACT

Scedosporium species are common fungal pathogens in patients with cystic fibrosis (CF). To colonize the CF lungs, fungi must cope with the host immune response, especially the reactive oxygen species (ROS) released by phagocytic cells. To this aim, pathogens have developed various antioxidant systems, including superoxide dismutases (SODs) which constitute the first-line protection against oxidative stress. Interestingly, one of the S. apiospermum SOD-encoding genes (SODD gene) exhibits a glycosylphosphatidylinositol (GPI) anchor-binding site and encodes a conidial-specific surface SOD. In this study, a SODDΔ mutant was engineered from a non-homologous end joining-deficient strain (KU70Δ) of S. apiospermum. Compared to its parent strain, the double mutant KU70Δ/SODDΔ exhibited increased susceptibility to various oxidizing agents and triazole antifungals. In addition, the loss of SodD resulted in an increased intracellular killing of the conidia by M1 macrophages derived from human blood monocytes, suggesting the involvement of this superoxide dismutase in the evasion to the host defenses. Nevertheless, one cannot disregard an indirect role of the enzyme in the synthesis or assembly of the cell wall components since transmission electron microscopic analysis revealed a thickening of the inner cell wall layer of the conidia. Further studies are needed to confirm the role of this enzyme in the pathogenesis of Scedosporium infections, including the production of a recombinant protein and study of its protective effect against the infection in a mouse model of scedosporiosis.

PMID:34356954 | DOI:10.3390/jof7070575